This study looks at the use of three cycles of chemotherapy given prior to radiation therapy in patients with cancer of the oral cavity and evidence of prior exposure to Human Papilloma Virus (HPV). Patients with cancer of the oral cavity who have evidence of exposure to HPV have a better prognosis than those who do not have such evidence of exposure to HPV. The main hypothesis of this study is that using three cycles of chemotherapy prior to embarking on radiation therapy will allow the use of reduced doses of radiation therapy and, therefore, less radiation induced side-effects. The primary objective is to determine the activity of this pre-radiation chemotherapy strategy along with reduced dose levels of radiation with or without chemotherapy during the radiation phase. The effectiveness of the strategy will be assessed at three months following the completion of the radiation therapy phase and also at two years following completion of the radiation therapy.

Phase II Trial of Neoadjuvant Chemotherapy for HPV-Associated Squamous Cell Carcinoma of the Oropharynx Followed by Reduced Dose Radiotherapy/Chemoradiotherapy for Responders or Standard Dose Chemoradiotherapy for Non-Responders

The 3-month response rate will be estimated using standard methods for estimating proportions and their 95% one-sided confidence intervals (CIs). Comparison to the historical control data will be carried out using a chi-square test for comparing proportions (or a Fisher exact test if an expected cell frequency in the 2x2 table is less than 5).

Secondary Outcome Measures:

To define objective tumor response rates to induction chemotherapy and to subsequent radiation-based treatment, per RESIST version 1.1 criteria. [ Time Frame: Three months following completion of radiation therapy phase. ] [ Designated as safety issue: No ]

To define objective tumor response rates to induction chemotherapy and to subsequent radiation-based treatment, per RESIST version 1.1 criteria.

To assess progression-free survival at 2 years [ Time Frame: At two years following completion of radiation phase ] [ Designated as safety issue: No ]

Progression-free survival at 2 years.

To assess overall survival at 2 years. [ Time Frame: At two years following completion of radiation phase ] [ Designated as safety issue: No ]

To assess overall survival at 2 years.

To assess locoregional disease control at 2 years [ Time Frame: At two years following completion of radiation phase ] [ Designated as safety issue: No ]

To assess locoregional disease control at 2 years

3.5 To assess distant disease control at 2 years. [ Time Frame: At two years following completion of radiation phase ] [ Designated as safety issue: No ]

3.5 To assess distant disease control at 2 years.

Assessment of quality of life outcomes [ Time Frame: Baseline, during therapy and up to two years following completion of radiation phase ] [ Designated as safety issue: No ]

Patients should have adequate bone marrow function defined as an absolute peripheral granulocyte count (AGC at least 1500 cells/mm3 and platelet count at least 100,000 cells/mm3); adequate hepatic function with bilirubin less than 1.5x ULN (excluding Gilbert's disease); SGOT, SGPT and alkaline phosphatase must be within the normal range to be eligible for study.

Patients must have an untransfused hemoglobin of at least 9.0 grams/dL.

Patients should have no serious acute or chronic co-morbid condition, or acute infection, which in the judgment of the attending physician would affect administration of the induction chemotherapy regimens.

Patients must sign a study-specific informed consent form.

All of the above lab criteria must be verified within 28days of registration.

Exclusion Criteria:

Low p16 expressing tumor by IHC, or indeterminate p16 expression by IHC and negative or weak detection of high-risk HPV infection by ISH.

TxNx without residual measurable disease, T4, or N3 disease.

Significant cigarette smoking history, defined as >10 pack-years total lifetime exposure. Pack years is calculated as # packs smoked per day x # years smoking.

Patients with a history of another malignancy (excluding non melanoma skin cancers, and cancers treated > 3 years prior for which patient remains continuously disease free).

Men and women of childbearing potential (WOCBP) unwilling to consent to using effective contraception while on treatment and for at least 3 months thereafter. Note: WOCBP must be using an adequate method of contraception to avoid pregnancy throughout the study and for 3 months after the study in such a manner that the risk of pregnancy is minimized.

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01525927